N-(4-hydroxyphenyl)-all-trans-retinamide, also known as 4-HPR or fenretinide and having CAS registry number 65646-68-6, is described in U.S. Pat. Nos. 4,190,594 and 4,323,581 and has the following formula: ##STR1## 4-HPR protects against mammary cancer in rats induced with N-nitroso-N-methyl urea, and is less toxic when given orally to rats then retinoyl acetate and retinoic acid, See R. C. Moon et al., Cancer Research, Vol. 39, 1979, 1339-13464.
Prior art processes (Scheme 1) for preparing 4-HPR, use agents such as thionyl chloride or phosphorus trichloride for acyl chloride formation. ##STR2##
Common problems associated with using the above-described agents include the instability of retinoic acid and retinoyl chloride in their presence and their use disadvantageously results in the formation of a polymeric by-product which must be removed from the retinoyl chloride before conversion to 4-HPR. Additionally the formation of 4-HPR from retinoyl chloride with p-aminophenol requires heating. The use of the thionyl chloride method is also not amenable to scale-up because of the dilute concentrations of retinoid (.ltoreq.0.2M) necessary to obtain reasonable yields and the precipitated pyridine hydrochloride causes handling problems on a large scale. Further, generation of retinoyl chloride using phosphorus trichloride requires temperatures of at least 50.degree. C. to go to completion rapidly. Since solutions of retinoyl chloride are prone to light, heat, oxygen and base-catalyzed decomposition, these methods are simply not practical for scale up. Although these processes give acceptable yields (70-80%) on a small scale (0.1M), very low yields (20-25%) are obtained on scales greater than 1M. These low yields are due to the sensitivity of the retinoyl chloride intermediate and 4-HPR to light, heat, oxygen and base-catalyzed decomposition. See e.g. M. B. Sporn, A. B. Roberts, D. S. Goodman (eds.) The Retinoids, Vol. 1, 1984, Academic Press Inc., Orlando and A. R. Oyler, M. G. Motto, R. E. Naldi, K. L. Facchine, P. F. Hamburg, D. J. Burinsky, R. Dunphy, and M. L. Cotter, Tetrahedron, Vol. 45, 1989, 7679.
Since retinoic acid starting material is relatively costly, the intermediates and the final product (4-HPR) are sensitive, and the yields of available preparations are low for greater than small scale preparations, the efficiency advantages of a mild, high yield synthesis suitable for large scale (&gt;1M) production are apparent.
An alternative process for preparing retinoyl chlorides is disclosed in U.S. Pat. No. 4,743,400 to Maryanoff which issued May 10, 1988 (U.S. Pat. No. 4,743,400) which avoids the use of prior art chlorinating agents such as thionyl chloride or phosphorus trichloride and the problems described at column 1, lines 21 to column 2, line 9 therein. U.S. Pat. No. 4,743,400 discloses process for producing retinoyl chloride using a dimethylchloroformamidinium chloride as the chlorinating agent. The entire disclosure of U.S. Pat. No. 4,743,400 is hereby incorporated herein by reference.
The process of U.S. Pat. No. 4,743,400 avoids some of the problems associated with thionyl chloride and phosphorus trichloride for producing the reagent retinoyl chloride.
The use of retinoyl chloride to produce 4-HPR by conventional reaction with p-aminophenol, however, provides unacceptably low product yields at larger scales for the reasons described above, i.e. sensitivity of the retinoyl chloride reaction intermediate and the product 4-HPR to light, heat, oxygen and base-catalyzed decomposition.
It is therefore, an object of the present invention to provide a process for the preparation of 4-HPR which is amenable to large scale production at high yields. It is a further and interrelated object of this invention to develop mild conditions for the preparation of 4-HPR to minimize decomposition and provide an efficient and high yielding large scale synthesis of high purity 4-HPR.